Treatment-related complications pose a major limitation to long-term success in the field of transplantation. Therefore, the induction of specific transplantation tolerance, which would eliminate the need for chronic immunosuppression, remains a major goal of modern transplantation immunology. Previous studies from our laboratory have demonstrated that the establishment of mixed lymphohematopoietic chimerism provides an effective means for the induction of long-term transplantation tolerance across major histocompatibility barriers in mice. The presence of donor- derived elements in such mixed chimeras induces specific tolerance, while host-type antigen presenting cells maintain normal immunocompetence. The major goal of this proposal is to utilize a clinically applicable, non- lethal preparative regimen to permit establishment of mixed chimerism and transplantation tolerance in a preclinical, non-human primate model. Specifically, we will: l) establish the efficacy of the mixed chimerism approach as a means of inducing transplantation tolerance in cynomolgus monkeys: 2) investigate the mechanism of tolerance in this model, including studies of the role of fractionated bone marrow cell populations and of the vascularized allograft in the induction of tolerance; and 3) assess the effects of variables in the preparative regimen in order to make this protocol applicable to cadaver-donor transplantation in humans. Our preliminary data indicate that a preparative regimen comparable to that which was used previously in mice, but using fractionated sublethal radiation, is capable of producing multilineage lymphohematopoietic chimerism and long-term tolerance to renal allografts between fully MHC mismatched cynomolgus monkeys. Although the number of animals treated so far with this regimen is small, mixed chimerism and tolerance appear to have been induced in all recipients. If confirmed and extended, with appropriate modifications of the timing of the preparative regimen, these results could have important clinical applications in the field of transplantation.